Structural Basis of Epitope Recognition by Heavy-Chain Camelid Antibodies.

TitleStructural Basis of Epitope Recognition by Heavy-Chain Camelid Antibodies.
Publication TypeJournal Article
Year of Publication2018
AuthorsZavrtanik, U., J. Lukan, R. Loris, J. Lah, and S. Hadži
JournalJ Mol Biol
Volume430
Issue21
Pagination4369-4386
Date Published2018 10 19
ISSN1089-8638
KeywordsAnimals, Binding Sites, Binding Sites, Antibody, Camelidae, Camelids, New World, Crystallography, X-Ray, Epitopes, Immunoglobulin Heavy Chains, Models, Molecular, Protein Binding, Single-Domain Antibodies
Abstract

Truncated versions of heavy-chain antibodies (HCAbs) from camelids, also termed nanobodies, comprise only one-tenth the mass of conventional antibodies, yet retain similar, high binding affinities for the antigens. Here we analyze a large data set of nanobody-antigen crystal structures and investigate how nanobody-antigen recognition compares to the one by conventional antibodies. We find that nanobody paratopes are enriched in aromatic residues just like conventional antibodies, but additionally, they also bear a more hydrophobic character. Most striking differences were observed in the characteristics of the antigen's epitope. Unlike conventional antibodies, nanobodies bind to more rigid, concave, conserved and structured epitopes enriched with aromatic residues. Nanobodies establish fewer interactions with the antigens compared to conventional antibodies, and we speculate that high binding affinities are achieved due to less unfavorable conformational and more favorable solvation entropy contributions. We observed that interactions with antigen are mediated not only by three CDR loops but also by numerous residues from the nanobody framework. These residues are not distributed uniformly; rather, they are concentrated into four structurally distinct regions and mediate mostly charged interactions. Our findings suggest that in some respects nanobody-antigen interactions are more similar to the general protein-protein interactions rather than antibody-antigen interactions.

DOI10.1016/j.jmb.2018.09.002
Alternate JournalJ. Mol. Biol.
PubMed ID30205092
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